1. Field of the Invention
The invention generally relates to polyamine-bridged platinum compounds. In particular, the invention provides blocked polyamine-bridged platinum compounds for use as prodrugs.
2. Background of the Invention
Polynuclear platinum complexes represent a discrete class of anticancer agents, distinct in biological activity from the mononuclear cis-DDP (cisplatin) and its congeners (1). Within this class of compounds, a variety of structural types differing in geometry and coordination type is possible (2). FIG. 1 shows the most general structure for these compounds:
DNA is widely accepted to be the target of platinum-based anticancer agents. The platinum compounds form covalent bonds with DNA, preferably guanine, by displacement of at least one leaving group, usually chloride. FIG. 2 shows the distinct structural types obtainable simply by varying X, Y and Z between Cl and NH3 ligands. The class of most current interest has been the so-called 1,1/t,t series where bifunctional DNA binding is achieved by the displacement of chlorides present in the coordination sphere and trans to the diamine bridge. The general formula for this structural class is shown in FIG. 3 (where Y represents a linear polyamine linker such as a-d of the figure and only the terminal primary amines are bound to the platinum) and may comprise either dinuclear or trinuclear compounds as indicated. The first compound to enter clinical trials from this new structural class is the trinuclear compound designated BBR3464 (FIG. 3b) (3). Polyamine-bridged dinuclear platinum compounds are highly interesting second-generation analogs of BBR3464 because the hydrogen-bonding and electrostatic contributions of the central platinum-amine group in BBR3464 are replicated by the free, non-coordinated “central” quaternary nitrogens of the linear polyamine linker while the presence of two separate Pt—Cl bonds maintains the bifunctional binding mode on the DNA adducts (4). Preclinical investigations confirm the potency of these species with cytotoxicity in the nanomolar range (5).
An interesting feature of the structure-activity relationships within the general structure represented in FIGS. 1 and 3 is that the possibility of hydrogen-bonding and electrostatic interactions in the linker has been shown to greatly enhance the cellular uptake, cytotoxicity and antitumor activity in comparison to a simple diamine linker such as H2N(CH2)nNH2 (e.g. FIG. 3a). In agreement with this observation, all blocked polyamine-bridged compounds are 1-2 orders of magnitude less cytotoxic than their unblocked counterparts (6, 7). Since the only difference is the charge on the compound and the presence of the “central” protonated but non-platinated amine, it is reasonable to assume that these features account for the potent cytotoxicity, i.e. the cytotoxicity and antitumor activity is a function of the specific linking polyamine.
Unfortunately, the remarkable potency of these polyamine-bridged dinuclear platinum complexes results in an extremely narrow therapeutic index. It would be highly desirable to have available forms of polyamine-bridged platinum drugs with enhanced therapeutic indices so that optimal doses could be administered while minimizing toxic side effects. Further, it would be highly desirable to have available forms of these drugs which are capable of targeted or selective release of the highly cytotoxic species.